Genetic Basis for susceptibility to Experimental Autoimmune Encephalomyelitis

实验性自身免疫性脑脊髓炎易感性的遗传基础

基本信息

批准号：
7194269
负责人：
VIJAY K. KUCHROO
金额：
$ 37.66万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7194269
关键词：
5-(6)-carboxyfluorescein diacetate succinimidyl ester Address Adoptive Transfer Affect Alleles Alternative Splicing Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antigens Apis Autoimmune Diseases Autoimmune Process Autoimmunity Backcrossings Brassicaceae CD28 gene CTLA4 gene Cell Line Cell Proliferation Cell division Cells Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 3 Class Congenic Mice Congenic Strain Data Demyelinations Development Diabetes Mellitus Disease Disease Resistance Disease susceptibility Dyes Ear Encephalomyelitis Experimental Autoimmune Encephalomyelitis Folch-Pi apoprotein Generations Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Grant Haplotypes Human Immune response Immunization Inbred NOD Mice Inbred Strains Mice Individual Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Interleukin-10 Interleukin-4 Laboratories Lead Ligands Link Location Lymphoid Microsatellite Repeats Modeling Mouse Strains Multiple Sclerosis Mus Myelin Myelin Proteolipid Protein Names Numbers Oocytes Pathway interactions Peptides Peripheral Pertussis Toxin Phenotype Polygenic Traits Predisposition Principal Investigator Production RNA Splicing Research Personnel Resistance Role SJL Mouse SJL/J Mouse Self Tolerance Series Susceptibility Gene T-Cell Activation T-Lymphocyte Testing Thymus Gland Transgenic Mice Transgenic Organisms Twin Studies autoreactive T cell base congenic cytokine genetic analysis genetic element novel programs proteolipid protein 139-151 reconstitution response size tool

项目摘要

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is an animal model for human MS that can be induced in experimental animals by immunization with myelin antigens. Both familial aggregation and twin studies in MS and the difference in the susceptibility to EAE in inbred strains of mice suggest a genetic component to these diseases, however the precise cellular and genetic factors that contribute to disease susceptibility/ resistance have not been identified. To define the factors that control susceptibility to EAE, we performed cellular immunological and genetic analysis of highly susceptible SJL/J and resistant B10.S mice, both of which are of the same MHC (H-2S) haplotype. Using microsatellite markers in a backcross of SJL and B10.S mice, we identified multiple loci that show significant linkage to EAE susceptibility. Some of the same loci have also been identified in other autoimmune diseases particularly diabetes in NOD mice thus raising the possibility that the same genetic elements or "common autoimmune genes" may contribute to the susceptibility to multiple autoimmune diseases. One of the ways by which we can identify the mechanism by which genetic loci affect T cell responses, is to express transgenic TcRs on appropriate genetic and congenic backgrounds. However, there is no TcR transgenic mouse strain available that can develop EAE on the NOD background. To study the relationship between the EAE-susceptibility loci that we have identified and the diabetes loci to the type of T cell response and their role in EAE susceptibility/ resistance, we propose to: 1) First generate a TcR transgenic mouse specific for MOG 35-55 on the NOD background so that the effect of resistance and susceptibility alleles on the development of encephalitogenic T cells can be tested. The TcR transgenic mice will also be tested for T cell selection, cytokine production, spontaneous and induced EAE. 21 Define genetic elements responsible for the difference in EAE susceptibility in the congenic intervals on NOD chromosome 1, named Idd5.2 and Idd5.3. Since the Idd5.2 congenic interval makes EAE worse and the Idd5.3 protects against the development of EAE, we propose to identify the genetic elements that are responsible for these effects by reducing the intervals (Idd5.2, Idd5.3) and analyzing the effect on T cell responses. 2) Test the development of EAE and T cell proliferative and cytokine responses to myelin antigens in congenic strains of mice that we have generated by introducing individual EAE-susceptibility loci from the susceptible SJL strain onto the resistant B10.S background. These studies will define the cellular and genetic basis for the difference in susceptibility and resistance to EAE in two different strain combinations, which may lead to the identification of susceptibility genes in MS and help in the identification of the mechanisms that contribute to inflammation and demyelination in the CNS.

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是人类MS的动物模型，可以通过用髓磷脂抗原免疫在实验动物中诱导。在小鼠近交菌株中，在MS中的家族聚集和双研究均表明了这些疾病的遗传成分，但是尚未确定有助于疾病易感性/抗药性的精确细胞和遗传因素。为了定义控制EAE易感性的因素，我们对高度易感的SJL/J和耐药性B10.S小鼠进行了细胞免疫和遗传分析，这两者都是相同的MHC（H-2S）单倍型。在SJL和B10.S小鼠的后串中，使用微卫星标记，我们确定了多个基因座，这些基因座与EAE敏感性显着联系。在其他自身免疫性疾病中也发现了一些相同的基因座，特别是点头小鼠中的糖尿病，从而增加了相同的遗传元素或“常见自身免疫基因”可能导致对多种自身免疫性疾病的敏感性的可能性。我们可以确定遗传基因座影响T细胞反应的机制的方法之一是在适当的遗传和先天背景上表达转基因TCR。但是，没有可用的TCR转基因小鼠菌株可以在点头背景上发展EAE。要研究我们已经鉴定出的EAE敏感性基因座与T细胞反应类型的糖尿病基因座及其在EAE敏感性/抗性中的作用之间的关系，我们建议：1）首先生成针对MOG 35-55的TCR转基因鼠标在NOD背景上的TCR转基因小鼠，从而在NOD背景上产生了对电阻性和易感性细胞的效果。 TCR转基因小鼠还将测试T细胞选择，细胞因子产生，自发和诱导的EAE。 21定义了负责EAE易感性差异的遗传因素，以点头染色体1，称为IDD5.2和IDD5.3。由于IDD5.2先天间隔使EAE变得更糟，而IDD5.3可以防止EAE的发展，因此我们建议通过减少间隔（IDD5.2，IDD5.3）来确定对这些影响负责的遗传因素，并分析对T细胞反应的影响。 2）测试EAE和T细胞增殖和细胞因子对小鼠先天性菌株中对髓磷脂抗原的反应，我们通过将易感性SJL菌株的单个EAE敏感性基因座引入耐药性B10.s背景而产生。这些研究将定义两种不同菌株组合中对EAE的易感性和抗性的差异的细胞和遗传基础，这可能导致MS中易感基因的鉴定，并有助于鉴定有助于CNS中炎症和脱毛的机制。